Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.

G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function. -->
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Grant Information: R01 HL109264 United States HL NHLBI NIH HHS
Substance Nomenclature: 0 (DSC2 protein, human)
0 (Desmocollins)
Entry Date(s): Date Created: 20061223 Date Completed: 20070206 Latest Revision: 20200824
Update Code: 20221213
PubMed Central ID: PMC1698714
DOI: 10.1086/509044
PMID: 17186466
Autor: Heuser A; Max-Delbrueck Center for Molecular Medicine, Franz-Volhard Clinic, HELIOS Clinics GmbH, Charité, Humboldt University, Berlin, Germany., Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B
Jazyk: angličtina
Zdroj: American journal of human genetics [Am J Hum Genet] 2006 Dec; Vol. 79 (6), pp. 1081-8. Date of Electronic Publication: 2006 Oct 03.
DOI: 10.1086/509044
Abstrakt: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor-site mutation in intron 5 (c.631-2A-->G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.
Databáze: MEDLINE
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